JPH09176149A - Substituted chromanyl sulfonyl (thio)urea compounds, their production, their use in medicinal preparation, and medicinal preparation containing their compounds - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new substituted chromanyl sulfonyl (thio)urea or its salt useful as an antiarrhythmic medicine used for treating all kinds of caused cardi ac arrhythmia and for preventing sudden heart death due to the cardiac arrhyth mia.

SOLUTION: This chromanyl sulfonyl (thio)urea is expressed by formula I [R(1) is H, an alkyl, an alkoxy, etc.; R(2a) is H, an alkyl; R(2b), R(2d) are each H, an alkyl, phenyl; R(2c), R(2e) are each H, an alkyl; R(3) is H, an alkyl, a cycloalkyl, etc.; Q is (CH₂)_n ((n) is 1, 2); Z is S, O; A is phenyl, a group of formula II, etc.,] or its medicinally acceptable salt, e.g. 4-(5-chloro-2- methoxybenzamidomethyl)-6-(methylaminocarbonylaminosulfonyl)-7- methoxychroman. The compound of formula I, e.g. a compound of formula III, is obtained by reacting a sulfamoylchroman of formula IV or its salt of formula V with a R(3)-substituted isocyanate.

COPYRIGHT: (C)1997,JPO

Description

Detailed Description of the Invention

The present invention relates to a compound of the formula I

Embedded image Of substituted chromanylsulfonyl (thio) ureas and physiologically acceptable salts thereof.

R (1) is hydrogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, fluorine, chlorine, bromine, iodine, CF ₃ , NH ₂ , 1 to 4 NH alkyl having 4 carbon atoms, N (alkyl) ₂ having 1 to 4 carbon atoms in the same or different alkyl groups or S-alkyl having 1 to 4 carbon atoms; R (2a) is , Hydrogen or alkyl having 1 or 2 carbon atoms; R (2b) and R (2d) are the same or different and are hydrogen, alkyl having 1 or 2 carbon atoms, unsubstituted phenyl, Substituted phenyl, unsubstituted benzyl or hydrogen present as a substituent in the phenyl group in the phenyl group, halogen,
R (2c) is benzyl substituted with up to 3 identical or different substituents selected from the group consisting of alkyl having 1 or 2 carbon atoms and alkoxy having 1 or 2 carbon atoms; ) And R (2e) are the same or different and are hydrogen or alkyl having 1 or 2 carbon atoms; R (3) is hydrogen, 1, 2, 3
Or alkyl having 4 carbon atoms, cycloalkyl having 3, 4, 5 or 6 ring carbon atoms, 3,
4,5 or CH ₂ having six ring carbon atoms - cycloalkyl, or CF _3; Q is an (CH _{2) n;}
n is 1 or 2; Z is sulfur or oxygen; A is unsubstituted or hydrogen, halogen, 1
Phenyl substituted by up to 3 identical or different substituents selected from the group consisting of alkyl having 1 or 2 carbon atoms and alkoxy having 1 or 2 carbon atoms, or A Is the expression

Embedded image Where B is 3, 4, 5 or 6 carbon atoms which is unsubstituted or substituted by up to 3 identical or different alkyl groups having 1, 2, 3 or 4 carbon atoms. Is a saturated or unsaturated lactam group (which is an alkenylene or alkylene) having

Embedded image Is a bicyclic group.

Preferred compounds of formula I are those in which R (1) is hydrogen,
Alkyl having 1 or 2 carbon atoms, alkoxy having 1 to 4 carbon atoms, fluorine, chlorine, bromine, iodine or CF ₃ ; R (2a), R (2b) and R (2d)
Are the same or different and are hydrogen or alkyl having 1 or 2 carbon atoms; R (2c) and R (2e) are hydrogen; R (3) is hydrogen or 1, 2, 3 or Four
Q is (CH ₂ ) _n ; n is 1 or 2; Z is sulfur or oxygen; A is unsubstituted or hydrogen, halogen, 1
Is phenyl substituted by up to 3 identical or different substituents selected from the group consisting of alkyl having 1 or 2 carbon atoms and alkoxy having 1 or 2 carbon atoms, or A is of the formula

Embedded image Where B is 3, 4, 5 or 6 carbons which are unsubstituted or substituted with up to 3 identical or different alkyl groups having 1, 2, 3 or 4 carbon atoms. A saturated or unsaturated lactam group (which is an alkenylene or alkylene having atoms) or A is of the formula

Embedded image Which is a group of the bicyclic system.

Particularly preferred compounds of formula I are those in which R (1) is hydrogen, alkyl having 1 or 2 carbon atoms, alkoxy having 1 or 2 carbon atoms, fluorine, chlorine, bromine, iodine or CF ₃ ; R (2a), R (2b),
R (2c), R (2d) and R (2e) are hydrogen; R (3) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; Q is (CH ₂ ) _n N is 1 or 2; Z is sulfur or oxygen; A is unsubstituted or hydrogen, halogen, alkyl having 1 or 2 carbon atoms and 1 or 2 carbon atoms Is phenyl substituted by up to 3 identical or different substituents selected from the group consisting of alkoxy having

Embedded image Where B is 3, 4, 5 or 6 carbons which are unsubstituted or substituted by up to 3 identical or different alkyl groups having 1, 2, 3 or 4 carbon atoms. A saturated or unsaturated lactam group (which is an alkenylene or alkylene having atoms) or A is of the formula

Embedded image Which is a group of the bicyclic system.

A very particularly preferred compound of formula I is R
(1) is hydrogen, an alkyl group having 1 or 2 carbon atoms or an alkoxy having 1 or 2 carbon atoms; R (2a), R (2b), R (2c), R ( 2d) and R (2
e) is hydrogen; R (3) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; Q is (CH ₂ ) _n
N is 1 or 2; Z is sulfur; A is unsubstituted or hydrogen, halogen, alkyl having 1 or 2 carbon atoms and 1 or 2 carbon atoms. Is phenyl substituted with up to three identical or different substituents selected from the group consisting of alkoxy having or A is of the formula

Embedded image Where B is 3, 4, 5 or 6 carbon atoms which is unsubstituted or substituted by up to 3 identical or different alkyl groups having 1, 2, 3 or 4 carbon atoms. Is a group of saturated or unsaturated lactams) which is alkenylene or alkylene;

Embedded image Which is a group of the bicyclic system.

Also very particularly preferred compounds of formula I are those in which R (1) is hydrogen, alkyl having 1 or 2 carbon atoms or alkoxy having 1 or 2 carbon atoms; R (1 2a), R (2b), R (2c), R (2d) and R (2e) are hydrogen; R (3) is hydrogen, methyl or ethyl; Q is (CH ₂ ) _n ; n is 1 or 2; Z is sulfur; A is unsubstituted or from hydrogen, halogen, alkyl having 1 or 2 carbon atoms and alkoxy having 1 or 2 carbon atoms. Is phenyl substituted by up to three identical or different substituents selected from the group or A is of the formula

Embedded image Where B is 3, 4, 5 or 6 carbon atoms which is unsubstituted or substituted by up to 3 identical or different alkyl groups having 1, 2, 3 or 4 carbon atoms. Is a alkenylene or alkylene) having a saturated or unsaturated lactam group.

Very particularly particularly preferred compounds of the formula I are:
R (1) is hydrogen, alkyl having 1 or 2 carbon atoms or alkoxy having 1 or 2 carbon atoms; R (2a), R (2b), R (2c), R ( 2d) and R (2
e) is hydrogen; R (3) is hydrogen, methyl or ethyl; Q is CH ₂ ; Z is sulfur; A is unsubstituted or hydrogen, halogen, 1 or 2 Is a phenyl substituted with up to 3 identical or different substituents selected from the group consisting of alkyl having 1 carbon atom or alkoxy having 1 or 2 carbon atoms.

Similarly, very particularly preferred compounds of formula I are those in which R (1) is hydrogen, alkyl having 1 or 2 carbon atoms or alkoxy having 1 or 2 carbon atoms; R (2a), R (2b), R (2c), R (2d) and R (2e) are hydrogen; R (3) is hydrogen or an alkyl having 1, 2, 3 or 4 carbon atoms. Yes; Q is (C
H ₂ ) _n ; n is 1 or 2; Z is oxygen; A is unsubstituted or hydrogen, halogen, 1
Is phenyl substituted by up to 3 identical or different substituents selected from the group consisting of alkyl having 1 or 2 carbon atoms or alkoxy having 1 or 2 carbon atoms, or A is of the formula

Embedded image Where B is 3, 4, 5 or 6 carbon atoms which is unsubstituted or substituted by up to 3 identical or different alkyl groups having 1, 2, 3 or 4 carbon atoms. Is a saturated or unsaturated lactam group (which is an alkenylene or alkylene) having

Embedded image Which is a group of the bicyclic system.

Also very particularly preferred compounds of formula I are those in which R (1) is hydrogen, alkyl having 1 or 2 carbon atoms or alkoxy having 1 or 2 carbon atoms; 2a), R (2b), R (2c), R (2d) and R (2e) are hydrogen; R (3) is hydrogen, methyl or ethyl; Q is (CH ₂ ) _n ; n is 1 or 2; Z is oxygen; A is unsubstituted or from hydrogen, halogen, alkyl having 1 or 2 carbon atoms and alkoxy having 1 or 2 carbon atoms. Is phenyl substituted by up to three identical or different substituents selected from the group or A is of the formula

Embedded image Where B is 3, 4, 5 or 6 carbon atoms which is unsubstituted or substituted by up to 3 identical or different alkyl groups having 1, 2, 3 or 4 carbon atoms. Is a alkenylene or alkylene) having a saturated or unsaturated lactam group.

Very particularly preferred compounds of formula I are likewise R (1) being hydrogen, alkyl having 1 or 2 carbon atoms or alkoxy having 1 or 2 carbon atoms; R (1 2a), R (2b), R (2c), R (2d) and R (2e) are hydrogen; R (3) is hydrogen, methyl or ethyl; Q is CH ₂ ; Z is oxygen And A is unsubstituted or hydrogen, halogen, 1 or 2
A compound which is phenyl substituted with up to 3 identical or different substituents selected from the group consisting of alkyl having 1 carbon atom and alkoxy having 1 or 2 carbon atoms.

R (2a) is preferably hydrogen. The term alkyl, unless stated otherwise, is a straight-chain or branched saturated hydrocarbon radical. This also applies to alkyl groups contained in alkoxy groups. Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of alkylene and alkenylene groups represented by group B are 1,3-propylene, 1,4-butylene, 1,5-pentylene, 1,6-hexylene, 1,3.
-Prop-1-enylene, 1,3-prop-2-enylene, 1,4-but-1-enylene, 1,4-but-2-enylene, 1,4-but-3-enylene, 1,5 -Pent-
1-enylene, 1,5-pent-2-enylene, 1,5-
Pent-3-enylene and 1,5-pent-4-enylene. In a substituted phenyl group which may be present on its own or in a benzyl group, the substituents are in the case of mono-substitution, for example in the ortho-, meta- or para-position, in the case of di-substitution, 2, Three
-2,4-, 2,5-, 2,6-, 3,4- or 3,5
In the case of the -position or tri substitution, for example, 2,3,4-,
It may be in any desired position in the 2,3,5-, 2,3,6- or 3,4,5-position. Halogen means, unless otherwise specified, fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

In addition, compounds of formula I can be present which have a chiral center, for example on carbon atoms 2, 3, 4 of a suitable substituted chroman system. In this case, the invention provides all possible stereoisomers, enantiomers and diastereomers, and also mixtures of two or more stereoisomers in any desired ratio, such as levorotatory and dextrorotatory. Enantiomerically pure forms of the enantiomers related to the sex enantiomer and also mixtures of the two enantiomers in various proportions are included.

The compounds of formula I are useful pharmaceutically active compounds for human and veterinary medicine, in particular for the treatment of cardiac arrhythmias and reduced contractility of the heart. Furthermore, these compounds can be used as intermediates for the production of other pharmaceutically active compounds. For certain benzenesulfonylureas, a hypoglycemic effect has been described. The prototype of such a hypoglycemic sulfonylurea is glibenclamide, which has been used therapeutically as an agent to treat diabetes and is of great relevance in the investigation of so-called ATP-sensitive calcium channels. It is useful for research as a tool with a certain nature. In addition to its hypoglycemic effect, glibenclamide has other effects, which, up until now, cannot be used therapeutically, are just the property of blocking these ATP-sensitive potassium channels. These include especially for antifibrillation of the heart. However,
In the treatment of ventricular fibrillation or its early stages, the concomitant lowering of blood glucose is undesirable and even dangerous as it can further exacerbate the patient's disease. European Patent Publication EP-A-612 724 discloses benzenesulfonylureas having an action on the cardiovascular system. However, the action is still unsatisfactory in many respects. Chromanil derivatives are neither described nor suggested therein.

EP-A-325,946 describes chroman compounds as α ₂ -adrenergic antagonists which have an effect on depression, metabolic disorders, glaucoma, migraine and hypertension. However, it does not describe or suggest any compounds substituted by sulfonylurea or sulfonylthiourea groups. The invention further relates to a process for preparing a compound of formula I which comprises the reaction steps shown below.

(A) a chromanylsulfonylurea of the formula I in which R (3) has other meanings other than hydrogen and Z is oxygen, has the formula (II)

Embedded image Sulfamoyl chroman or formula III

Embedded image A salt thereof of formula IV R (3) -N = C = O (IV) with an R (3) -substituted isocyanate of formula I
a (Z = O in formula I)

Embedded image Can be prepared by obtaining the substituted chromanyl sulfonylurea.

The groups in the formulas II, III and IV have the meanings given initially. Suitable cations M in the salts of formula III are, for example, alkali metal, alkaline earth metal, ammonium and tetraalkylammonium ions. Similar to the R (3) -substituted isocyanates of formula IV, R (3) -substituted carbonic acid derivatives such as R (3)
It is possible to use -substituted carbamic acid esters, R (3) -substituted carbamoyl halides or R (3) -substituted ureas.

(B) a chromanylsulfonylurea of formula I in which R (3) is hydrogen and Z is oxygen is a sulfamoylchroman of formula II or a salt thereof of formula III and a trialkylsilylisocyanate or a silicon tetrachloride. It can be prepared by reaction with isocyanates and cleavage (eg hydrolysis) of the mainly formed silicon-substituted chromanylsulfonylureas. In addition, sulfamoylchroman of formula II or a salt of formula III of R (3) by reaction with a cyanogen halide and hydrolysis of the predominantly formed N-cyanosulfonamide with a mineral acid at temperatures between 0 ° C and 100 ° C. ) Is hydrogen and Z is oxygen can be converted to the chromanylsulfonylurea of formula I.

(C) Formula Ia wherein Z in Formula I is oxygen.
Chromanyl sulphonylurea of formula V is an R (3) -substituted formula V on a nitrogen in the presence of a base in an inert solvent according to Synthesis 1987, 734-735 at a temperature of 25 ° C to 150 ° C.

Embedded image Can be prepared from the sulfamoylchroman of formula II or its salt of formula III using trichloroacetamide of

Suitable bases are, for example, alkali metal or alkaline earth metal hydroxides, hydrides, amides or also alkoxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium hydride, potassium hydride, Calcium hydride, sodium amide, potassium amide, sodium methoxide, sodium ethoxide, potassium methoxide or potassium ethoxide. Suitable inert solvents are ethers such as tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, diglyme, ketones such as acetone or butanone, nitriles such as acetonitrile, nitro compounds such as nitromethane, esters such as ethyl acetate, amides such as dimethylformamide ( DMF) or N-methylpyrrolidone (NMP), hexamethylphosphoric triamide, sulfoxides such as DMSO, sulfones such as sulfolane, hydrocarbons such as benzene, toluene, xylene. Furthermore, mixtures of these solvents with one another are also suitable.

(D) Formula Ib in which Z in Formula I is sulfur.
Chromanyl sulfonyl thiourea

Embedded image Can be prepared from sulfamoylchroman of formula II or a salt thereof of formula III and an R (3) -substituted isocyanate of formula VI R (3) -N = C = O (VI).

(E) A chromanylsulfonylthiourea of the formula I in which R (3) is hydrogen and Z is sulfur is of the formula II
Of sulfamoylchroman of formula III or a salt thereof of formula III with a trialkylsilylisothiocyanate, such as trimethylsilylisothiocyanate or silicon tetraisothiocyanate, and cleavage of the predominantly formed silicon-substituted chromanylsulfonylthiourea (e.g. Can be manufactured by decomposition). In addition, the sulfamoylchroman of formula II or its salt of formula III is reacted with benzoyl isothiocyanate and the intermediate benzoyl-substituted chromanylsulfonylthiourea is reacted with aqueous mineral acid to give R (3) = H Equation 1b that is
Can be obtained. A similar method is described in J. Med.
Chem. 1992, 35, 1137-1144. Yet another variant consists in reacting the N-cyanosulfonamide described in method (b) with hydrogen sulphide.

(F) The substituted chromanylsulfonylureas of formula Ia can be prepared by a conversion reaction from the chromanylsulfonylthioureas of formula Ib. Desulfurization, ie the replacement of a sulfur atom in an appropriately substituted chromanyl sulfonylthiourea by an oxygen atom, is also possible, for example with the aid of oxides or salts of heavy metals or also like hydrogen peroxide, sodium peroxide or nitrous acid. It can be carried out by using an oxidizing agent. Thiourea can also be desulfurized by treatment with a chlorinating agent such as phosgene or phosphorus pentachloride. Chloroform amidine or carbodiimide is obtained as an intermediate,
These compounds can be converted into the corresponding substituted chromanylsulfonylureas, for example by hydrolysis or addition of water.

(G) Chromanylsulfonylureas of the formula I in which Z is oxygen are R (3) -substituted ureas or R (3)-
Using a substituted bis (trialkylsilyl) urea, for example, a compound of formula VII

Embedded image Can be prepared from the chromanyl sulfonyl halide. In addition, the sulfonyl chloride of formula VII can be reacted with parabanic acid to give chromanylsulfonylparabanic acid which can be hydrolyzed with mineral acid to give the corresponding chromanylsulfonylurea of formula I (Z = O). it can.

(H) Chromanylsulfonylureas of the formula I in which Z is oxygen are obtained by converting the amine of R (3) -NH ₂ into the formula VIII

Embedded image It can be produced by reacting with chromanyl sulfonyl isocyanate.

The sulfonyl isocyanate of formula VIII can be obtained from the sulfamoylchroman of formula II by conventional methods, for example using phosgene. formula
As described above for the isocyanate of VIII, the amine R (3) -NH ₂ is reacted with a chromanylsulfonylcarbamate ester, a carbamoyl halide or a chromanylsulfonylurea of formula Ia wherein R (3) is hydrogen and Z is oxygen. A compound of formula I can be obtained.

(I) A chromanyl sulfonylthiourea of the formula I in which Z is sulfur is obtained by converting the amine of the formula R (3) -NH ₂ into the formula IX

Embedded image Can be obtained by reacting with chromanyl sulfonyl isothiocyanate.

Similarly, the amine R (3) -NH ₂ can be reacted with chromanylsulfonylcarbamic acid thioester or -carbamoylthiohalide to give compounds of formula I where Z is sulfur. The sulfonylisothiocyanate of formula IX can be prepared by reacting the corresponding sulfonamide with an alkali metal hydroxide and carbon disulfide in an organic solvent such as DMF, DMSO or N-methylpyrrolidone. The dialkali metal salt of the sulfonyldithiocarbamic acid thus obtained is reacted with a chloroformate (2 equivalents) or with thionyl chloride in an inert solvent with a slight excess of phosgene or a phosgene substitute such as triphosgene. Can be made. The solution of the sulfonylisothiocyanate thus obtained can be reacted directly with the corresponding amine or ammonia.

(J) Appropriately substituted chromanyl sulphenyl- or sulphinyl ureas can be converted to Z using an oxidizing agent such as hydrogen peroxide, sodium peroxide or nitrous acid.
Chromanylsulfonylureas of formula I can be obtained in which is oxygen. Starting materials for the methods described above for the synthesis of chromanylsulfonylureas of formula I are described in the literature (eg Houben-Weyl, Methoden der Organischen Chemie.
[Methods of Organic Chemistry], Georg Thieme Ver
lag, Stuttgart: Organic Reactions, John Wiley & So
ns, Inc., New York; and methods known per se, such as those described in standard textbooks such as ns, Inc., New York; and the patent applications referred to above). In this case, it is possible to use variants which are known per se, but are not mentioned here in great detail. If desired, the starting materials can also be formed in-situ for further reaction directly without isolation from the reaction mixture.

4-Aminoalkylchromans are described in, for example, European Patent Publication EP-A-325 964 and US Pat. Nos. 5,140,039 or 5,185,364, or in these patent specifications. It can be produced by the method described. The appropriately substituted amine of formula XI is acylated according to scheme 1 to formula XI
The amide of I can be obtained and then subjected to halosulfonation. Suitable acylating agents for amino groups are advantageously alkyl esters, halides (for example chloride or bromide) of carboxylic acids of the formula R (5) COY or anhydrides. In this regard, R (5) is a trihalomethyl group or (C _1-
A C ₄ ) -alkyl group or R (5) COY has the formula A
COY (A according to the meaning of this group as described above is substituted or unsubstituted phenyl and Y
Is a benzoic acid derivative of a halide, (C ₁ -C ₄ ) -alkoxy, a trihaloacetate or a leaving group such as (C ₁ -C ₄ ) -carboxylate).

[0030]

Embedded image

The synthesis of compounds of formula XII is usually carried out by the addition of a tertiary base such as pyridine or trialkylamine in the presence or absence of an inert solvent. It is also possible to add a catalyst such as dimethylaminopyridine. The reaction is carried out at about
It can be achieved at temperatures of ° C, preferably 20-150 ° C. The acyl group of the compound of formula XII can be a protecting group, or in the case of benzoic acid derivatives,
That is, when R (5) is A, it has the meaning of A described above, which is part of the compound of formula I. Suitable inert solvents are
Ethers such as tetrahydrofuran, dioxane, glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether, diglyme, ketones such as acetone or butanone, nitriles such as acetonitrile, amides such as dimethylformamide ( DMF) or N-methylpyrrolidone (NMP), hexamethylphosphoric triamide, sulfoxides such as DMSO, chlorinated hydrocarbons such as dichloromethane, chloroform, trichloroethylene,
1,2-dichloroethane or carbon tetrachloride, hydrocarbon,
For example, benzene, toluene or xylene. Furthermore, mixtures of these solvents with one another are also suitable.

In a compound of formula I, the group A has the formula B as defined above.

Embedded image Or is a group of formula

Embedded image The acylated amine corresponding to the formula XII can be prepared as follows.

First, the amine of formula XI is converted to an isocyanate or a reactive carbonic acid derivative. Conversion of amine XI to isocyanate (Scheme 2) is

Embedded image A compound of XI in the presence of a tertiary alkyl amine or pyridine and an inert solvent, a carbonyl halide,
It can be carried out in a known manner, for example by reacting with phosgene or triphosgene. Suitable inert solvents are ethers such as tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, diglyme, ketones such as acetone or butanone, nitriles such as acetonitrile, nitro compounds such as nitromethane, esters such as ethyl acetate, amides such as dimethylformamide ( DMF) or N-methylpyrrolidone (NMP), hexamethylphosphoric triamide, sulfoxides such as DMSO, sulfones such as sulfolane, hydrocarbons such as benzene, toluene or xylene. Furthermore, mixtures of these solvents with one another are also suitable. Suitable reactive carbonic acid derivatives are carbonic acid esters such as can be synthesized from alkyl chloroformates and XI and a suitable tertiary alkyl amine or pyridine. In addition, N, N'-carbonyldiimidazole and similar reactive derivatives can also be used as isocyanate substitutes (Staab, HA Synthesen mit he.
terocyclischen Amiden (Azoliden) 〔Syntheses with
heterocyclic amides (azolides)], Angewandte Chemi
e 74 (1962), No. 12 407-423).

Isocyanates of the formula XIIa or the corresponding urethanes are then introduced into the second molecular component, for example in the presence or absence of an inert solvent, for example 100
A formula having the meaning of B above at ˜170 ° C.

Embedded image Or a compound of the formula

Embedded image (Justus Liebigs Ann. Ch.
em. 1956, 598, 203) and an acylurea derivative of formula XIIb corresponding to formula XII in which A is a heterocyclic group as described above (Scheme 3).

[0035]

Embedded image

Formula X obtained by Scheme 1 or 2/3
The acylated amines of II and XIIb can be converted to the sulfonamides of formula II by known methods. The sulfonamides of the formula II are prepared by methods known per se, ie under known and suitable conditions for the reaction. In this case, variants known per se can be used, which are not mentioned here in great detail. If desired, the synthesis can be accomplished in one, two or more steps. In particular, the formula XII or XIIb
-10 ° C to 120 ° C, preferably 0 ° C to 10 ° C, in the presence or absence of an inert solvent.
A method in which an aromatic sulfonic acid or a derivative thereof, for example, a sulfonyl halide is converted with an electrophile at a temperature of 0 ° C. is preferable. For example, sulfonation can be carried out using sulfuric acid or fuming sulfuric acid or halosulfonation can be carried out by reaction with halosulfonic acid, reaction with sulfuryl halide in the presence of anhydrous metal halide or anhydrous metal halide. With a thionyl halide in the presence of ## STR4 ## then using known oxidation practices to give the sulfonyl chloride. If the sulphonic acids are the primary reaction products, these can be used directly or with tertiary amines such as pyridine or trialkylamines, alkali metal or alkaline earth metal hydroxides or in the reaction system. Conversion to a sulfonyl halide by known methods with acid halides such as phosphorus trihalide, phosphorus pentahalide, phosphorus oxychloride, phosphorus oxychloride, thionyl halide or oxalyl halide by treatment with a reagent which forms a basic compound of can do. This sulphonic acid derivative can be converted into a sulphonamide by methods known from the literature. Preferably, the sulfonyl chloride is reacted with aqueous ammonia in an inert solvent at a temperature of 0-100 ° C. Further, the sulfonamide can be prepared by a method described in the literature at -100 to 50 ° C, preferably -100 ° C to 30
Prepared according to Scheme 1 by reaction with an alkali metal or alkaline earth metal organometallic reagent at a temperature of ° C in an inert gas atmosphere and in an inert solvent, reaction with sulfur dioxide and subsequent heat treatment with amidosulfonic acid. Can be synthesized from the acylated amine of formula XII.

If the acyl group R (5) CO functions as a protecting group for the amino group in the compounds of the formula XI, this can be removed with an acid or base after the preparation of the sulfonamides of the formula IIa. Cleavage by an acid in an aqueous acid or an inert solvent can form the corresponding acid addition salt. For example, sulfuric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, phosphoric acid, such as orthophosphoric acid or polyphosphoric acid or other conventional acids capable of cleaving amides are suitable for this reaction. Cleavage of the acylated amine of formula XII with a base can also be carried out in an aqueous or inert solvent. Suitable bases are, for example, alkali metal or alkaline earth metal hydroxides or alkoxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium hydride, sodium methoxide, sodium ethoxide, potassium methoxide or potassium. Ethoxide.

From sulfonamide-substituted amines prepared in this way or their acid addition compounds, sulfamoylchromans of the formula II in which the nitrogen atom carries the acyl radical ACO can be prepared as described above. . When isolated, R (1), R (2a), R (2b), R (2c),
Depending on the nature of R (2d), R (2e), R (3), Z, Q and A, one or the other method of preparing the compounds of formula I is inappropriate or at least Requires protection of reactive groups. Cases of this type, which occur relatively rarely, can be recognized by the person skilled in the art without difficulty and in such cases the other synthetic methods described above can be used without difficulty.

The compounds of formula I can have one or more chiral centers. When one or more chiral centers are present, compounds of formula I having a uniform stereochemistry at these centers are preferred. The compounds of formula I having one or more chiral centers can be obtained as racemates in their preparation or, if optically active starting materials are used, in optically active form. can get. If the compound has two or more chiral centers, the compound may be obtained synthetically as a mixture of racemates from which the individual isomers may be purified by recrystallization, for example from an inert solvent. Can be isolated in various forms. If desired, the racemates obtained can be mechanically or chemically separated into enantiomers by methods known per se. That is, diastereomers can form from the racemates by reaction with an optically active resolving agent. Suitable resolving agents for basic compounds are, for example, optically active acids, eg tartaric acid in the R- or R, R- and S- or S, S-form, dibenzoyltartaric acid, diacetyltartaric acid, camphor sulphonic acid, mandelic acid. ,
Malic acid or lactic acid. The various forms of diastereomers can be separated in a manner known per se, for example by fractional crystallization, and the enantiomers of the formula I can be separated from diastereomers in a manner known per se. Furthermore, the separation of enantiomers is performed by chromatography on an optically active support material. A particularly simple method of preparing optically uniform compounds is, for example, by resolution of the amine of formula XI into the enantiomers by recrystallization with an optically active acid, such as (+)-or (−)-mandelic acid. It then consists of converting to the final compound of formula I which is partially enantiomerically pure as described above.

The compounds of formula I and their physiologically acceptable salts are not only suitable as antiarrhythmic agents, but also in humans or mammals (eg monkeys, dogs, mice, rats,
It is a useful therapeutic agent for the treatment and prevention of cardiovascular, heart failure, heart transplant and cerebrovascular disease in rabbits, guinea pigs, cats and large producer animals such as cattle and pigs. The physiologically acceptable salts of the compounds of formula I are Re
mmington's Pharmaceutical Science, 17th Edition 19
85, pp. 14-18, eg formula X

Embedded image Is understood to mean a compound of This compound can be prepared from non-toxic organic and inorganic bases and chromanyl sulfonyl (thio) ureas of formula I.
In this regard, preferred salts are compounds in which the cation M'in formula X is a sodium, potassium, rubidium, calcium, magnesium or ammonium ion or an ammonium ion having an organic group, and also compounds of formula I and basic amino acids, such as It is a compound that is an acid addition product of lysine or arginine. This salt is prepared by conventional procedures, eg in a solvent or diluent, with a compound of formula I in a suitable base, eg sodium hydroxide,
It can be obtained by reacting with potassium hydroxide or an amine. Suitable physiologically acceptable salts in the case of compounds of formula I having a basic group are furthermore:
Addition products with non-toxic inorganic and organic acids and these addition products can likewise be obtained by combining the components, for example in suitable solvents or diluents. Suitable acids are, for example, sulfuric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, phosphoric acid, such as orthophosphoric acid or polyphosphoric acid, sulfamic acid, and also organic acids, especially aliphatic, cycloaliphatic, araliphatic, aromatic compounds. Or a heterocyclic mono- or polybasic carboxylic acid, sulfonic acid or sulfuric acid, such as acetic acid, propionic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid,
Maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2- or 3-phenylpropionic acid, phenylacetic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, Ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemono- and-disulfonic acid or laurylsulfuric acid.

The compounds of the present invention are particularly useful pharmaceuticals for treating cardiac arrhythmias of all kinds of causes and for preventing sudden cardiac death due to arrhythmias and therefore can be used as antiarrhythmic agents. it can. Examples of cardiac arrhythmia diseases are supraventricular arrhythmias, such as atrial tachycardia, atrial flutter or paroxysmal supraventricular arrhythmias or ventricular arrhythmias, such as ventricular premature contractions, especially life-threatening ventricular tachycardia or Particularly dangerous ventricular fibrillation. They are particularly suitable, in particular when the arrhythmia is a result of coronary vasoconstriction, such as occurs during acute infarction in angina or as a result of the chronic infarction. Therefore, these compounds are particularly suitable for the prevention of sudden cardiac death in patients after infarction.

Furthermore, a clinical manifestation in which this type of arrhythmia and / or sudden cardiac death due to arrhythmia plays a role is cardiac hypertrophy, for example as a result of cardiac dysfunction or chronically elevated blood pressure. In addition, the compounds of the invention can improve the reduction in cardiac contractility. Relevant to the present application is a disease-related reduction in cardiac contraction in acute cases, such as heart failure and / or heart failure as a result of the action of shock. Similarly, in the case of heart transplants, the heart is
The functional ability can be restored more rapidly and reliably. The same applies to surgery on the heart, which requires a temporary suspension of cardiac activity with a cardioplegic solution.

The compounds of formula I and their physiologically acceptable salts according to the invention can be used for the manufacture of pharmaceutical preparations. In this regard, these compounds are combined with at least one solid or liquid excipient or adjuvant, either on their own or in combination with other drugs, for example drugs having cardiovascular activity such as calcium antagonists or ACE inhibitors. Together with a suitable dosage form. Pharmaceutical compositions containing a pharmaceutical formulation and an effective amount of one or more compounds of the compound of formula I or physiologically acceptable salts thereof, the use of the compounds in the manufacture of pharmaceutical compositions and such pharmaceutical compositions A method of manufacturing an article is likewise a subject of the present invention. These formulations can be used as human or veterinary medicine.

Excipients which can be used are organic or anhydrous substances which are suitable for enteral (eg oral) or parenteral (eg intravenous) administration or topical application and which do not react with the compounds of the formula I, For example, water, vegetable oils, alcohols such as ethanol, propanediol or benzyl alcohol, polyethylene glycol, polypropylene glycol, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, lanolin, or petrolatum. In particular, pharmaceutical forms such as tablets, coated tablets, capsules, suppositories, solutions, preferably oily or aqueous solutions, syrups, juices or drops and additionally suspensions or emulsions are used for oral and rectal administration. You can Ointment, cream, paste, lotion, gel,
Sprays, foams, aerosols, solutions (eg alcohols such as ethanol, propanol or 1,2-
Propanediol or these solvents or in a mixture with one another or with water) or powders are used for topical application. Further suitable pharmaceutical forms are eg implants. The compounds of formula I can also be lyophilized and the lyophilizates obtained used, for example, for the preparation of injectable formulations. In particular, liposomal formulations are also suitable for topical application. Pharmaceutical preparations include lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts (eg salts which affect permeation pressure), buffer substances, colorants and flavors and / or
Or it may contain auxiliaries such as fragrances.
If desired, the composition may also contain one or more other active compounds, such as one or more vitamins.

The dosage required to treat a cardiac arrhythmia using a compound of formula I will depend on whether the treatment is acute or prophylactic and will depend on the particular individual case.
Usually, when prophylactic treatment is carried out, about at least 0.01 mg / kg / day, preferably 0.1 mg / kg, especially 1 mg / kg / day.
~ At most 100 mg, preferably 10 mg is suitable.
Particularly suitable is 1 to 10 mg per kg per day. In this case, the doses are given individually orally or parenterally or in divided doses, for example up to 4 times. In the case of treatment of acute cardiac arrhythmia,
Parenteral administration is advantageous, for example in the intensive care unit, by injection or infusion. A preferred dosage range in dangerous situations is 10 to 100 mg, which can be administered, for example, by continuous intravenous infusion.

Apart from the compounds mentioned in the examples, the compounds of the formula I, for example, shown below, can also be obtained according to the invention. 4- (5-chloro-2-methoxybenzamidomethyl)
-6- (Methylaminocarbonylaminosulfonyl)-
7-ethylchroman 4- (5-bromo-2-methoxybenzamidomethyl)
-6- (Methylaminocarbonylaminosulfonyl)-
7-ethylchroman 4- (5-bromo-2-methoxybenzamidomethyl)
-6- (Methylaminothiocarbonylaminosulfonyl) -7-methoxychroman 4- (5-chloro-2-methoxybenzamidoethyl)
-6- (Methylaminocarbonylaminosulfonyl)-
7-Ethylchroman 4- (5-chloro-2-methoxybenzamidoethyl)
-6- (Methylaminothiocarbonylaminosulfonyl) -7-methoxychroman 4- (5-bromo-2-methoxybenzamidoethyl)
-6- (Methylaminocarbonylaminosulfonyl)-
7-ethyl chroman 4- (5-bromo-2-methoxybenzamidoethyl)
-6- (Methylaminothiocarbonylaminosulfonyl) -7-methoxychroman 4- (5-chloro-2-methoxybenzamidoethyl)
-6- (Methylaminocarbonylaminosulfonyl)-
7-methoxychroman 4- (5-chloro-2-methoxybenzamidoethyl)
-6- (Methylaminothiocarbonylaminosulfonyl) -7-ethoxychroman 4- (5-chloro-2-methoxybenzamidomethyl)
-6- (ethylaminocarbonylaminosulfonyl)-
7-ethylchroman 4- (5-bromo-2-methoxybenzamidomethyl)
-6- (ethylaminocarbonylaminosulfonyl)-
7-ethylchroman 4- (5-bromo-2-methoxybenzamidomethyl)
-6- (Ethylaminothiocarbonylaminosulfonyl) -7-methoxychroman 4- (5-chloro-2-methoxybenzamidoethyl)
-6- (ethylaminocarbonylaminosulfonyl)-
7-Ethylchroman 4- (5-chloro-2-methoxybenzamidoethyl)
-6- (Ethylaminothiocarbonylaminosulfonyl) -7-methoxychroman 4- (5-bromo-2-methoxybenzamidoethyl)
-6- (ethylaminocarbonylaminosulfonyl)-
7-ethyl chroman 4- (5-bromo-2-methoxybenzamidoethyl)
-6- (Ethylaminothiocarbonylaminosulfonyl) -7-methoxychroman 4- (5-chloro-2-methoxybenzamidoethyl)
-6- (ethylaminocarbonylaminosulfonyl)-
7-methoxychroman 4- (5-chloro-2-methoxybenzamidoethyl)
-6- (Ethylaminothiocarbonylaminosulfonyl) -7-ethoxychroman 4- (5-fluoro-2-methoxybenzamidomethyl) -6- (ethylaminocarbonylaminosulfonyl) -7-methoxychroman 4- (5-fluoro 2-Methoxybenzamidomethyl) -6- (methylaminocarbonylaminosulfonyl) -7-methylchroman 4- (5-fluoro-2-methoxybenzamidomethyl) -6- (methylaminothiocarbonylaminosulfonyl) -7-methyl Chroman 4- (5-fluoro-2-methoxybenzamidomethyl) -6- (methylaminocarbonylaminosulfonyl) -7-ethylchroman 4- (5-fluoro-2-methoxybenzamidomethyl) -6- (methylaminothiocarbonyl) Aminosulfonyl -7-Ethylchroman 4- (5-Fluoro-2-methoxybenzamidomethyl) -6- (methylaminocarbonylaminosulfonyl) -7-ethoxychroman 4- (5-Fluoro-2-methoxybenzamidomethyl) -6- ( Methylaminothiocarbonylaminosulfonyl) -7-ethoxychroman 4- (5-fluoro-2-methoxybenzamidomethyl) -6- (ethylaminocarbonylaminosulfonyl) -7-ethoxychroman 4- (5-fluoro-2-methoxy Benzamidomethyl) -6- (ethylaminothiocarbonylaminosulfonyl) -7-ethoxychroman 4-((3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) ethyl) -6- (methyl Aminothiocarbonylaminosulfonyl) -7-d Chicycloman 4-((3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) ethyl) -6- (methylaminocarbonylaminosulfonyl) -7-ethoxychroman 4-((3-ethyl- 4-Methyl-2-oxo-3-pyrroline-1-carboxamido) ethyl) -6- (methylaminothiocarbonylaminosulfonyl) -7-ethylchroman 4-((3-ethyl-4-methyl-2-oxo- 3-Pyrroline-1-carboxamido) ethyl) -6- (methylaminocarbonylaminosulfonyl) -7-ethylchroman 4-((2-oxo-3-pyrroline-1-carboxamido) ethyl) -6- (methylaminothio Carbonylaminosulfonyl) -7-ethoxychroman 4-((2-oxo-3-pyrroline-1-carboxyl Samido) ethyl) -6- (methylaminocarbonylaminosulfonyl) -7-ethoxychroman 4-((2-oxo-3-pyrroline-1-carboxamido) ethyl) -6- (methylaminothiocarbonylaminosulfonyl) -7 -Ethylchroman 4-((2-oxo-3-pyrroline-1-carboxamido) ethyl) -6- (methylaminocarbonylaminosulfonyl) -7-ethylchroman 4-((2-oxo-3-pyrroline-1- Carboxamido) ethyl) -6- (methylaminothiocarbonylaminosulfonyl) -7-ethoxychroman 4-((2-oxo-3-pyrroline-1-carboxamido) ethyl) -6-methylaminocarbonylaminosulfonyl) -7- Ethoxychroman

Example 1 4- (5-chloro-2-methoxybenzamidomethyl)
-6- (Methylaminocarbonylaminosulfonyl)-
7-methoxychroman

Embedded image 4- (5-chloro-2-methoxybenzamidomethyl)
-6-Sulfamoyl-7-methoxychroman 1.76
g (4 mmol) was dissolved in 10 ml of dry DMSO,
And 0.4 g (10 mmol) of ground sodium hydroxide and 1.05 of N-methyltrichloroacetamide.
After addition of g (6 mmol), the mixture was stirred at 80 ° C for 30
Heat for a minute. The cooled reaction mixture was introduced into ice water,
Clean with activated carbon and acidify to pH 1. The precipitate is filtered off with suction, dried and recrystallized twice from ethanol / DMF. 4- (5-Chloro-2-methoxybenzamidomethyl) -6- (methylaminocarbonylaminosulfonyl) -7-methoxychroman having a melting point of 207 ° C. is obtained. Preparation of the starting compound 4- (5-chloro-2-methoxybenzamidomethyl) -6-sulfamoyl-7-methoxychroman 4-Aminomethyl-7-methoxychroman hydrochloride 14.
8 g (64.4 mmol) are dissolved in 75 ml pyridine and treated with 13.4 g 2-methoxy-5-chlorobenzoyl chloride while cooling to 0 ° C. The mixture is stirred at room temperature for 1.5 hours and 60 ° C. for 1 hour. The cooled reaction mixture is partitioned between water and methylene chloride. The aqueous phase is extracted 3 times with methylene chloride. The combined organic phase,
Wash with 2N hydrochloric acid, water and bicarbonate solution. An oil was obtained after drying and evaporation of the organic phase. 20g of this oil
Cooled to -20 ° C and cooled to 30 chlorosulfonic acid
Add ml with stirring. The mixture is brought to room temperature with shaking and a further 5 ml of chlorosulfonic acid are added. After stirring in ice water, the precipitate obtained is filtered off with suction and washed with a little cold water, then acetone 20 cooled to -20.degree.
It is introduced into a solution of 0 ml and 120 ml of concentrated ammonia. After allowing the mixture to warm to room temperature and stand overnight, the solution is concentrated in vacuo. The residue is treated with concentrated hydrochloric acid with ice cooling. The precipitate obtained is filtered off with suction and recrystallized from glacial acetic acid / methanol. 4- (5-Chloro-2-methoxybenzamidomethyl) -6-sulfamoyl-7-methoxychroman is obtained in the form of colorless crystals with a melting point of 202 ° C.

Example 2 4- (5-chloro-2-methoxybenzamidomethyl)
-6- (ethylaminocarbonylaminosulfonyl)-
7-methoxychroman

Embedded image 4- (5-chloro-2-methoxybenzamidomethyl)
-6- (ethylaminocarbonylaminosulfonyl)-
7-methoxychroman was replaced with 4- (5-chloro-2-methoxybenzamidomethyl) -6-sulfamoyl-7-.
Prepared as in Example 1 from methoxychroman and N-ethyltrichloroacetamide. Melting point 211
~ 213 ° C.

Example 3 4- (5-chloro-2-methoxybenzamidomethyl)
-6- (n-Propylaminocarbonylaminosulfonyl) -7-methoxychroman

Embedded image 4- (5-chloro-2-methoxybenzamidomethyl)
-6- (n-Propylaminocarbonylaminosulfonyl) -7-methoxychroman was added to 4- (5-chloro-2
Prepared in analogy to example 1 from -methoxybenzamidomethyl) -6-sulfamoyl-7-methoxychroman and N- (n-propyl) trichloroacetamide. 159-160 ° C.

Example 4 4- (5-chloro-2-methoxybenzamidomethyl)
-6- (Methylaminothiocarbonylaminosulfonyl) -7-methoxychroman

Embedded image 1.76 g (4 mmol) of 4- (5-chloro-2-methoxybenzamidomethyl) -6-sulfamoyl-7-methoxychroman from Example 1 was dissolved in 5 ml of dry DMF and 1.65 g of potassium carbonate and isothiocyanic acid. Treat with 0.35 g (4.8 mmol) of methyl. 8
After stirring for 1 hour at 0 ° C., the mixture is cooled and introduced into ice water, cleaned with carbon and acidified to pH 1. The precipitate is filtered off with suction, dried and recrystallized from ethanol / DMF. Melting point 121 [deg.] C.

Example 5 4- (5-chloro-2-methoxybenzamidomethyl)
-6- (Ethylaminothiocarbonylaminosulfonyl) -7-methoxychroman

Embedded image 4- (5-chloro-2-methoxybenzamidomethyl)
-6- (Ethylaminothiocarbonylaminosulfonyl) -7-methoxychroman was added to 4- (5-chloro-2
Prepared as described in Example 4 from -methoxybenzamidomethyl) -6-sulfamoyl-7-methoxychroman and ethyl isothiocyanate. Melting point 1
96-197 ° C.

Example 6 4- (5-chloro-2-methoxybenzamidomethyl)
-6- (n-Propylaminothiocarbonylaminosulfonyl) -7-methoxychroman

Embedded image 4- (5-chloro-2-methoxybenzamidomethyl)
-6- (n-Propylaminothiocarbonylaminosulfonyl) -7-methoxychroman was added to 4- (5-chloro-2-methoxybenzamidomethyl) -6-sulfamoyl-7-methoxychroman and isothiocyanic acid n.
Prepared from propyl as described in Example 4. 183-184 ° C.

Example 7 4- (5-chloro-2-methoxybenzamidomethyl)
-6- (Isopropylaminothiocarbonylaminosulfonyl) -7-methoxychroman

Embedded image 4- (5-chloro-2-methoxybenzamidomethyl)
-6- (Isopropylaminothiocarbonylaminosulfonyl) -7-methoxychroman was treated as in Example 4 with 4- (5-chloro-2-methoxybenzamidomethyl) -6-sulfamoyl-7-methoxychroman and isothiocyanate. Made from isopropyl acid. 184-185 ° C.

Example 8 4- (5-chloro-2-methoxybenzamidomethyl)
-6- (n-Butylaminothiocarbonylaminosulfonyl) -7-methoxychroman

Embedded image 4- (5-chloro-2-methoxybenzamidomethyl)
-6- (n-Butylaminothiocarbonylaminosulfonyl) -7-methoxychroman was added to 4- (5-chloro-
2-methoxybenzamidomethyl) -6-sulfamoyl-7-methoxychroman and isothiocyanate n-
Prepared in the same manner as in Example 4 from butyl. Melting point 16
7 ° C.

Example 9 4- (5-chloro-2-methoxybenzamidomethyl)
-6- (Methylaminocarbonylaminosulfonyl)-
7-ethoxychroman

Embedded image 4- (5-chloro-2-methoxybenzamidomethyl)
-6- (Methylaminocarbonylaminosulfonyl)-
7-Ethylchroman is prepared from 4- (5-chloro-2-methoxybenzamidomethyl) -6-sulfamoyl-7-ethoxychroman and N-methyltrichloroacetamide as described in Example 1. Melting point 207-208 [deg.] C. Preparation of the starting compound 4- (5-chloro-2-methoxybenzamidomethyl) -6-sulfamoyl-7-ethoxychroman

Embedded image 4- (5-chloro-2-methoxybenzamidomethyl)
-6-sulfamoyl-7-ethoxychroman, 4-
Prepared analogously to the starting compound described in Example 1, starting from aminomethyl-7-ethoxychroman and 5-chloro-2-methoxybenzoyl chloride. The intermediate formed in this way is then treated with chlorosulfonic acid,
Then react with ammonia to give 4- (5-chloro-2-
Methoxybenzamidomethyl) -6-sulfamoyl-
7-Ethoxychroman is obtained. 204-205 ° C.

Example 10 4- (5-chloro-2-methoxybenzamidomethyl)
-6- (Methylaminothiocarbonylaminosulfonyl) -7-ethoxychroman

Embedded image 4- (5-chloro-2-methoxybenzamidomethyl)
-6- (Methylaminothiocarbonylaminosulfonyl) -7-ethoxychroman was added to 4- (5-chloro-2
Prepared from -methoxybenzamidomethyl) -6-sulfamoyl-7-ethoxychroman and methyl isothiocyanate as described in Example 4. Melting point 2
02 ° C.

Example 11 4- (5-Fluoro-2-methoxybenzamidomethyl) -6- (methylaminocarbonylaminosulfonyl) -7-methoxychroman

Embedded image 4- (5-Fluoro-2-methoxybenzamidomethyl) -6- (methylaminocarbonylaminosulfonyl) -7-methoxychroman was converted into 4- (5-fluoro-
Prepared in analogy to example 1 from 2-methoxybenzamidomethyl) -6-sulfamoyl-7-methoxychroman and N-methyltrichloroacetamide. Melting point 193-194 [deg.] C. Preparation of the Starting Compound 4- (5-Fluoro-2-methoxybenzamidomethyl) -6-sulfamoyl-7-methoxychroman

Embedded image 4- (5-fluoro-2-methoxybenzamidomethyl) -6-sulfamoyl-7-methoxychroman,
Example 1 starting from 4-aminomethyl-7-methoxychroman and 2-methoxy-5-fluorobenzoic acid
It is manufactured in the same manner as described above. The intermediate is sulfochlorinated as described in Example 1 and then reacted with ammonia to give the corresponding sulfamoyl compound. Melting point 206
° C.

Example 12 4- (5-Fluoro-2-methoxybenzamidomethyl) -6- (methylaminothiocarbonylaminosulfonyl) -7-methoxychroman

Embedded image 4- (5-Fluoro-2-methoxybenzamidomethyl) -6- (methylaminothiocarbonylaminosulfonyl) -7-methoxychroman was added to 4- (5-fluoro-2-methoxybenzamidomethyl) -6-sulfamoyl-7. Obtained analogously to Example 4 by reaction of -methoxychroman with methyl isothiocyanate. Melting point 19
4 ° C.

Example 13 4- (5-Fluoro-2-methoxybenzamidomethyl) -6- (ethylaminothiocarbonylaminosulfonyl) -7-methoxychroman

Embedded image 4- (5-Fluoro-2-methoxybenzamidomethyl) -6- (ethylaminothiocarbonylaminosulfonyl) -7-methoxychroman was added to 4- (5-fluoro-2-methoxybenzamidomethyl) -6-sulfamoyl-7. Obtained as described in Example 4 from methoxychroman and ethyl isothiocyanate. Melting point 2
07 ° C.

Example 14 4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl) -6- (methylaminothiocarbonylaminosulfonyl) -7-methoxychroman

Embedded image 4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl) -6-sulfamoyl-7-methoxychroman 1.27 g (3 mmol), finely powdered potassium carbonate 1.24 g (9 mmol) and 0.292 g (4 mmol) methyl isothiocyanate are suspended or dissolved in 12 ml DMSO. The reaction mixture is stirred at 80 ° C. for 1 hour. The mixture is poured into ice water and the product is acidified with hydrochloric acid to precipitate.
After filtering off with suction and drying, the crude product is chromatographed on silica gel (eluent: 9: 1 methylene chloride /
(Glacial acetic acid). 115 ° C. Starting compound 4-((3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl) -6-
Preparation of sulfamoyl-7-methoxychroman

Embedded image 4-aminomethyl-7-methoxychroman 7.33 g
(38 mmol) was dissolved in 50 ml of tetrahydrofuran, and 6.16 g of N, N'-carbonyldiimidazole (3
8 mmol) is added. The mixture is stirred at room temperature for 1 hour then evaporated in vacuo. 3-ethyl-4-methyl-
2-oxo-3-pyrroline 4.76 g (38 mmol)
Is added to the residue and the mixture is heated at 160-170 ° C. for 2 hours. It is chromatographed on silica gel using 3: 1 ethyl acetate / petroleum ether as eluent and 4-((3-ethyl-4
-Methyl-2-oxo-3-pyrroline-1-carboxamido) methyl) -7-methoxychroman is obtained. This product is introduced into chlorosulfonic acid cooled to -15 ° C. in a conventional manner. The mixture is allowed to come to room temperature and stirred for 1 hour. After conventional treatment, the sulfochloride is converted to the sulfonamide as described in Example 1. 4-((3
-Ethyl-4-methyl-2-oxo-3-pyrroline-1
-Carboxamido) methyl) -6-sulfamoyl-7
-Methoxychroman has a melting point of 235-236 ° C.

Example 15 4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl) -6- (ethylaminothiocarbonylaminosulfonyl) -7-methoxychroman

Embedded image 4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl) -6- (ethylaminothiocarbonylaminosulfonyl) -7-methoxychroman was converted into 4-((3- Ethyl-4-methyl-2-oxo-2-pyrroline-1-carboxamido) methyl) -6
Prepared as in Example 14 from -sulfamoyl-7-methoxychroman and ethyl isothiocyanate. 147 ° C.

Example 16 4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl) -6- (n-propylaminothiocarbonylaminosulfonyl) -7-methoxychroman

Embedded image 4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl) -6- (n-propylaminothiocarbonylaminosulfonyl) -7-methoxychroman was converted into 4-(( 3-ethyl-4-methyl-2
Prepared from -oxo-3-pyrroline-1-carboxamido) methyl) -6-sulfamoyl-7-methoxychroman and n-propyl isothiocyanate as described in Example 14. 96-98 ° C.

Example 17 4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl) -6- (isopropylaminothiocarbonylaminosulfonyl) -7-methoxychroman

Embedded image 4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl) -6- (isopropylaminothiocarbonylaminosulfonyl) -7-methoxychroman was converted into 4-((3- Ethyl-4-methyl-2
Example 1 starting from -oxo-3-pyrroline-1-carboxamido) methyl) -6-sulfamoyl-7-methoxychroman and isopropyl isothiocyanate.
It synthesize | combines like 4. 153 ° C.

Example 18 4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl) -6- (methylaminocarbonylaminosulfonyl) -7-methoxychroman

Embedded image 0.5 g of 4-((3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl) -6- (methylaminothiocarbonylaminosulfonyl) -7-methoxychroman (Example 14) Is dissolved in 10 ml of cold 0.5N sodium hydroxide solution. 0.5 ml of 37% strength hydrogen peroxide solution are added cold (-4 ° C to 0 ° C) and the mixture is stirred at 0 ° C for 1 hour. The product is precipitated by the addition of 2N HCl. The crude product is purified by chromatography on silica gel (eluent: 9: 1 methylene chloride / glacial acetic acid). Melting point 211 [deg.] C.

Example 19 4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl) -6- (ethylaminocarbonylaminosulfonyl) -7-methoxychroman

Embedded image 4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl) -6- (ethylaminocarbonylaminosulfonyl) -7-methoxychroman was treated with 37% strength hydrogen peroxide. 4- using the solution
Similar to Example 18 by oxidizing ((3-ethyl-4-methyl-2-oxo-3-pyrrolidinyl-1-carboxamido) methyl) -6- (ethylaminothiocarbonylaminosulfonyl) -7-methoxychroman. To get. Melting point 188-189 [deg.] C.

Example 20 4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl) -6- (methylaminothiocarbonylaminosulfonyl) -7-ethoxychroman

Embedded image 4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl) -6- (methylaminothiocarbonylaminosulfonyl) -7-ethoxychroman was converted into 4-((3- Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl) -6
Synthesized as in Example 14 from -sulfamoyl-7-ethoxychroman and methyl isothiocyanate. Melting point 178 [deg.] C. Starting compound 4-((3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl) -6-
Preparation of sulfamoyl-7-ethoxychroman

Embedded image 9.5 ml (0.1 mol) of boron trifluoride was added to 4-((3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamide) in 75 ml of methylene chloride cooled to -10 ° C.
Methyl) -6-sulfamoyl-7-methoxychroman was added dropwise to a solution of 10.6 g (0.025 mol). 20 ° C
After allowing to stand at room temperature overnight, the excess boron trifluoride is cooled to -10 ° C, and methanol is carefully added dropwise to decompose it. Then the mixture is introduced into ice / water and extracted several times with methylene chloride. The combined methylene chloride extracts are dried, evaporated and recrystallized from methanol. 4 with a melting point of 175 ° C
-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl) -6-sulfamoyl-7-hydroxychroman is obtained. Ethyl iodide 2.1
6 ml (0.027 mol) of 4- in 60 ml of acetone
((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl) -6-sulfamoyl-7-hydroxychroman 9 g (0.022 mol) and potassium carbonate 6.1 g (0.044). Mol) suspension. After stirring under reflux for 3 hours, the mixture is introduced into ice / water and carefully acidified with concentrated hydrochloric acid. The precipitate is filtered off with suction, washed several times with cold water, dried and ethanol / DM
Recrystallize from F. 4-((3-ethyl-
4-Methyl-2-oxo-3-pyrroline-1-carboxamido) methyl) -6-sulfamoyl-7-ethoxychroman is obtained.

Example 21 4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl) -6- (ethylaminothiocarbonylaminosulfonyl) -7-ethoxychroman

Embedded image 4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl) -6- (ethylaminothiocarbonylaminosulfonyl) -7-ethoxychroman was converted into 4-((3- Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl) -6
Synthesized analogously to Example 14, starting from -sulfamoyl-7-ethoxychroman and isothiocyanic acid. Melting point 178-180 [deg.] C.

Example 22 4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl) -6- (methylaminocarbonylaminosulfonyl) -7-ethoxychroman

Embedded image 4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl) -6- (methylaminocarbonylaminosulfonyl) -7-ethoxychroman was prepared in the same manner as in Example 18. , 4-((3-ethyl-4-methyl-2-oxo-3 using hydrogen peroxide solution)
Synthesized by oxidation of -pyrroline-1-carboxamido) methyl) -6- (methylaminothiocarbonylaminosulfonyl) -7-ethoxychroman. Melting point 187-
188 ° C.

Example 23 4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl) -6- (ethylaminocarbonylaminosulfonyl) -7-ethoxychroman

Embedded image 4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl) -6- (ethylaminocarbonylaminosulfonyl) -7-ethoxychroman was prepared in the same manner as in Example 18. , 4-((3-ethyl-4-methyl-2-oxo-3 using hydrogen peroxide solution)
Obtained by oxidation of -pyrroline-1-carboxamido) methyl) -6- (ethylaminothiocarbonylaminosulfonyl) -7-ethoxychroman. Melting point 175 [deg.] C.

Example 24 (+)-4- (5-chloro-2-methoxybenzamidomethyl) -6- (methylaminocarbonylaminosulfonyl) -7-methoxychroman

Embedded image (+)-4- (5-chloro-2-methoxybenzamidomethyl) -6- (methylaminocarbonylaminosulfonyl) -7-methoxychroman was added to the optically active 4-
(5-chloro-2-methoxybenzamidomethyl) -6
Prepared as in Example 1 from -sulfamoyl-7-methoxychroman and N-methyltrichloroacetamide. Melting point 242 ° C; [α] _D ²⁰ : + 63.4 °
(C = 1, DMF); HPLC: ee 100%. Example 1
For the synthesis of the starting compound prepared as described in (4), 4-aminomethyl-7-methoxychroman dextrorotatory mandelate (physicochemical data of the mandelate: melting point 144 ° C .; [α] _D ²⁰ : +57 0.5 ° (c = 1, H
₂ O); HPLC: ee 93.8%).

Example 25 (+)-4- (5-chloro-2-methoxybenzamidomethyl) -6- (methylaminothiocarbonylaminosulfonyl) -7-methoxychroman

Embedded image (+)-4- (5-chloro-2-methoxybenzamidomethyl) -6- (methylaminothiocarbonylaminosulfonyl) -7-methoxychroman was added to the optically active 4
-(5-chloro-2-methoxybenzamidomethyl)-
Prepared as described in Example 4 from 6-sulfamoyl-7-methoxychroman and methyl isothiocyanate. Melting point 201 ° C; [α] _D ²⁰ : + 47.2 °
(C = 1, DMF); HPLC: ee88.1%.

Example 26 (-)-4- (5-chloro-2-methoxybenzamidomethyl) -6- (methylaminocarbonylaminosulfonyl) -7-methoxychroman

Embedded image (−)-4- (5-Chloro-2-methoxy-benzamidomethyl) -6- (methylaminocarbonylaminosulfonyl) -7-methoxychroman was added to the optically active 4-
(5-chloro-2-methoxybenzamidomethyl) -6
Prepared as in Example 1 from -sulfamoyl-7-methoxychroman and N-methyltrichloroacetamide. Melting point: 239 ° C; [α] _D ²⁰ : -59.8 °
(C = 1, DMF). HPLC: ee 98.5%. For the synthesis of the starting compound prepared as described in Example 1, 4-aminomethyl-7-methoxychroman levorotatory mandelate (physicochemical data of the mandelate: melting point 147-148 ° C .; [α ] _D ²⁰ : -59.5 °
(C = 1, H ₂ O); HPLC: ee 99.1%) is used.

Example 27 (-)-4- (5-chloro-2-methoxybenzamidomethyl) -6- (methylaminothiocarbonylaminosulfonyl) -7-methoxychroman

Embedded image (-)-4- (5-Chloro-2-methoxybenzamidomethyl) -6- (methylaminothiocarbonylaminosulfonyl) -7-methoxychroman was added to the optically active 4
-(5-chloro-2-methoxybenzamidomethyl)-
Prepared as described in Example 4 from 6-sulfamoyl-7-methoxychroman and methyl isothiocyanate. Melting point: 202 ° C; [α] _D ²⁰ : -64.5 °
(C = 1, DMF); HPLC: ee 97.9%.

Pharmacological Data The following model can be used to demonstrate the therapeutic properties of the compounds of formula I. Action potential period on guinea pig papillary muscle (a) Introduction The ATP-deficient state as observed during ischemia in cardiomyocytes leads to a shortened action potential period. These are believed to be one of the causes of so-called reentry arrhythmias that can cause sudden cardiac death. Opening of ATP-sensitive K channels by lowering ATP is regarded as a causal link. (B) Method Standard microelectrode technology is used to measure action potentials. For this, guinea pigs of both sexes were killed by banging their heads, the hearts were removed and the papillary muscles were separated and suspended in an organic bath. The organic bath was placed in Ringer's solution (NaCl 0.9%, KCl 0.048).
%, CaCl ₂ 0.024%, NaHCO ₃ 0.02% and glucose 0.1%) and send a mixture of 95% oxygen and 5% carbon dioxide at a temperature of 36 ° C. Electrode with 1 V square-wave impulse and 1 ms
For a period of 2 Hz and a frequency of 2 Hz. 3M K induced action potential and inserted into cells
Record by glass microelectrodes filled with Cl solution. The test substance is added to the Ringer's solution at a concentration of 2.2 · 10 ⁻⁶ mol / l. Action potential is Hugo Sachs
Amplified on an oscilloscope using an amplifier from. The action potential duration is 95% (APD ₉₅ ) of repolarization (repol).
arization). The action potential decrease is caused by the calcium channel opener HOE 234 (Rilmakalim) (W.
Linz, E. Klaus, U. Albus, RHA Becker, D. Mani
a, HC Englert, BA Schoelkens, Arzneimittelfo
rschung / Drug Research, Volume 42 (11), 1992, 1180-
1185)) at 1 μM strength. The test substance was added to the bath solution as a stock solution in propanediol. The values given relate to the measurement 30 minutes after the addition. The comparative control is considered as APD ₉₅ in the presence of HOE 234 and in the absence of test substance. (C) Results The following values were measured.

[Table 1]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 405/12 211 C07D 405/12 211 (72) Inventor Deeater Mania Federal Republic of Germany 61462 Königishyutai N. Goethe Schutlerse 43 (72) Inventor Wolfgang Linz, Federal Republic of Germany 55129 Mainz. Fuchser Leben Vejk 54 (72) Inventor Heinz Gegerlein 60259 Frankfurt. Tsum Eiskeller 7 (72) Inventor Erik Klaus Federal Republic of Germany 65779 Kerkheim. Schwürth-Valto Schyutraße 50 (72) Inventor Peter Krause, Federal Republic of Germany 63069 Otufuembach. Schiopenhauer Schyutraße 31

Claims (19)

[Claims] 1. A compound of the formula I Chromanyl sulfonyl (thio) urea or a physiologically acceptable salt thereof. In the above formula, R (1) is hydrogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, fluorine, chlorine, bromine, iodine, CF ₃ , NH ₂ , 1 to NH alkyl having 4 carbon atoms, N (alkyl) ₂ having 1 to 4 carbon atoms in the same or different alkyl groups or S-alkyl having 1 to 4 carbon atoms; R (2
a) is hydrogen or alkyl having 1 or 2 carbon atoms; R (2b) and R (2d) are the same or different and are hydrogen, alkyl having 1 or 2 carbon atoms, substituted With phenyl, substituted phenyl, unsubstituted benzyl or hydrogen present as a substituent in a phenyl group in a phenyl group, a halogen, an alkyl having 1 or 2 carbon atoms and having 1 or 2 carbon atoms Benzyl substituted with up to 3 identical or different substituents selected from the group consisting of alkoxy; R (2c) and R (2e) are the same or different and are hydrogen or 1 or 2 carbon atoms. R (3) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5 or 6 ring carbon atoms. Kill, CH ₂ having 3, 4, 5 or 6 ring carbon atoms - cycloalkyl, or CF _3; Q is (CH ₂₎ be _n; n is 1 or 2; Z is Sulfur or oxygen; A is unsubstituted or three selected from the group consisting of hydrogen, halogen, alkyl having 1 or 2 carbon atoms and alkoxy having 1 or 2 carbon atoms. Is phenyl substituted by the same or different substituents up to, or A is of the formula: Where B is 3, 4, 5 or 6 carbon atoms which is unsubstituted or substituted by up to 3 identical or different alkyl groups having 1, 2, 3 or 4 carbon atoms. Is a saturated or unsaturated lactam group (which is an alkenylene or alkylene) having A or has the formula: Is a bicyclic group. 2. R (1) is hydrogen, 1 or 2 carbon atoms
Child-bearing alkyl, ar having 1 to 4 carbon atoms
Coxi, Fluorine, Chlorine, Bromine, Iodine or CF _ThreeIs;
R (2a), R (2b) and R (2d) are the same or different and
Elementary or alkyl having 1 or 2 carbon atoms
Yes; R (2c) and R (2e) are hydrogen; R (3) is water
An element having 1, 4, 3, or 4 carbon atoms
Rukiru; Q is (CH_Two)_nAnd n is 1 or 2
Yes; Z is sulfur or oxygen; A is not substituted
Squid or hydrogen, halogen, 1 or 2 carbon atoms
With an alkyl and 1 or 2 carbon atoms
Up to three same groups selected from the group consisting of
Phenyl substituted by one or different substituents
Or A is of the formulaWhere B is unsubstituted or 1, 2, 3 or
Or up to 3 identical or different with 4 carbon atoms
3, 4, 5 or substituted by an alkyl group
Alkenylene or alkylene having 6 carbon atoms
Is a saturated or unsaturated lactam group
Or A is of the formulaA compound of formula I according to claim 1 which is a bicyclic radical of 3. R (1) is hydrogen, alkyl having 1 or 2 carbon atoms, alkoxy having 1 or 2 carbon atoms, fluorine, chlorine, bromine, iodine or CF ₃ ; R (2a), R (2b), R (2c), R (2d) and R (2e) are hydrogen; R (3) is hydrogen or an alkyl having 1, 2, 3 or 4 carbon atoms. Yes; Q is (CH ₂ ) _n ; n is 1 or 2; Z is sulfur or oxygen; A is unsubstituted or hydrogen, halogen, 1
Is phenyl substituted by up to 3 identical or different substituents selected from the group consisting of alkyl having 1 or 2 carbon atoms and alkoxy having 1 or 2 carbon atoms, or A is of the formula [Chemical 6] Where B is 3, 4, 5 or 6 carbons which are unsubstituted or substituted by up to 3 identical or different alkyl groups having 1, 2, 3 or 4 carbon atoms. A saturated or unsaturated lactam group (which is an alkenylene or alkylene having atoms) or A is of the formula A compound of formula I according to claim 1 or 2 which is a bicyclic radical of 4. R (1) is hydrogen, an alkyl group having 1 or 2 carbon atoms or an alkoxy having 1 or 2 carbon atoms; R (2a), R (2b), R (2c),
R (2d) and R (2e) are hydrogen; R (3) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; Q is (CH ₂ ) _n ; n is 1 or 2; Z is sulfur; A is unsubstituted or hydrogen, halogen, alkyl having 1 or 2 carbon atoms and alkoxy having 1 or 2 carbon atoms. Is phenyl substituted with up to 3 identical or different substituents selected from, or A is of the formula: Where B is 3, 4, 5 or 6 carbon atoms which is unsubstituted or substituted by up to 3 identical or different alkyl groups having 1, 2, 3 or 4 carbon atoms. Is a saturated or unsaturated lactam group (which is an alkenylene or alkylene) having the formula; or A is of the formula: A compound of formula I according to any one of claims 1 to 3 which is a bicyclic radical of 5. R (1) is hydrogen, alkyl having 1 or 2 carbon atoms or alkoxy having 1 or 2 carbon atoms; R (2a), R (2b), R ( 2c), R
(2d) and R (2e) are hydrogen; R (3) is hydrogen, methyl or ethyl; Q is (CH ₂ ) _n ; n is 1 or 2; Z is sulfur; Up to three identical or different substitutions wherein A is unsubstituted or selected from the group consisting of hydrogen, halogen, alkyl having 1 or 2 carbon atoms and alkoxy having 1 or 2 carbon atoms. Phenyl substituted by minutes,
Or A is of the formula Where B represents 3, 4, 5 or 6 carbon atoms which are unsubstituted or substituted by up to 3 identical or different alkyl groups having 1, 2, 3 or 4 carbon atoms. An alkenylene or alkylene) having a saturated or unsaturated lactam group.
A compound of formula I according to any of paragraphs 4 to 4. 6. R (1) is hydrogen, alkyl having 1 or 2 carbon atoms or alkoxy having 1 or 2 carbon atoms; R (2a), R (2b), R ( 2c), R
(2d) and R (2e) are hydrogen; R (3) is hydrogen, methyl or ethyl; Q is (CH ₂ ) _n ; n is sulfur; A is unsubstituted or Hydrogen, halogen,
A phenyl substituted by up to 3 identical or different substituents selected from the group consisting of alkyl having 1 or 2 carbon atoms or alkoxy having 1 or 2 carbon atoms. A compound of formula I according to any of paragraphs 6. 7. R (1) is hydrogen, alkyl having 1 or 2 carbon atoms or alkoxy having 1 or 2 carbon atoms; R (2a), R (2b), R ( 2c), R
(2d) and R (2e) are hydrogen; R (3) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; Q is (CH ₂ ) _n ; n Is 1 or 2; Z
Is sulfur; A is unsubstituted or selected up to three selected from the group consisting of hydrogen, halogen, alkyl having 1 or 2 carbon atoms and alkoxy having 1 or 2 carbon atoms. Is phenyl substituted by the same or different substituents of, or A is of the formula Where B is 3, 4, 5 or 6 carbon atoms which is unsubstituted or substituted by up to 3 identical or different alkyl groups having 1, 2, 3 or 4 carbon atoms. Is a saturated or unsaturated lactam group (which is alkenylene or alkylene) having the formula: A compound of formula I according to any one of claims 1 to 3 which is a bicyclic radical of 8. R (1) is hydrogen, alkyl having 1 or 2 carbon atoms or alkoxy having 1 or 2 carbon atoms; R (2a), R (2b), R ( 2c), R
(2d) and R (2e) are hydrogen; R (3) is hydrogen, methyl or ethyl; Q is (CH ₂ ) _n ; n is 1 or 2; Z is sulfur; Up to three identical or different substitutions wherein A is unsubstituted or selected from the group consisting of hydrogen, halogen, alkyl having 1 or 2 carbon atoms and alkoxy having 1 or 2 carbon atoms. Phenyl substituted by minutes,
Or A is of the formula Where B is 3, 4, 5 or 6 carbon atoms which is unsubstituted or substituted by up to 3 identical or different alkyl groups having 1, 2, 3 or 4 carbon atoms. A compound of formula I according to any one of claims 1, 2, 3 and 7 which is a saturated or unsaturated lactam group of 9. R (1) is hydrogen, alkyl having 1 or 2 carbon atoms or alkoxy having 1 or 2 carbon atoms; R (2a), R (2b), R ( 2c), R
(2d) and R (2e) are hydrogen; R (3) is hydrogen, methyl or ethyl; Q is (CH ₂ ) _n ; Z is sulfur; A is unsubstituted or Hydrogen, halogen,
A phenyl substituted with up to 3 identical or different substituents selected from the group consisting of alkyl having 1 or 2 carbon atoms and alkoxy having 1 or 2 carbon atoms. A compound of formula I according to any one of paragraphs 2, 3, 7 and 8. 10. Formula II: Sulfamoylchroman of formula III or A salt of R (3)-, wherein the group has the meanings given in claim 1 and the cation M is, for example, an alkali metal, alkaline earth metal, ammonium or tetraalkylammonium ion. Substituted isocyanates or isothiocyanates, R (3) -substituted carbonic acid derivatives or reacted with R (3) -substituted trichloroacetamide on nitrogen; or a compound of formula I wherein R (3) is hydrogen To produce formula II or III
Of a compound of formula I, wherein Z is oxygen, by reacting a compound of To produce a compound, a compound of formula I where Z is sulfur is desulfurized; to produce a compound of formula I where Z is oxygen Reacting a compound of the formula ## STR15 ## with R (3) -substituted urea or bis (trialkyl) silylurea; or formula VIII or IX (Wherein, groups have the meanings indicated in Claim 1) preparation of a compound of formula R (3) consists in reacting an amine of -NH ₂ compound according to claim 1 of the formula I as claimed in. 11. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for the treatment of cardiac arrhythmias. 12. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for the prevention of sudden cardiac death. 13. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for the treatment of ischemic diseases of the heart. 14. Formula I according to claim 1 for producing a scientific tool that inhibits ATP-sensitive potassium channels.
Use of compounds. 15. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for the treatment of weakened myocardial contractile force. 16. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for improving heart function after heart transplantation. 17. Use of a compound of formula I according to claim 1 for the treatment and prevention of cardiovascular, cardiac arrhythmia, cardiac ischemic disease, weakened myocardial contractile disease or for the prevention of sudden cardiac death. . 18. Claims 1 to 1 for use as a medicament.
A compound of formula I according to at least one of item 9. 19. A pharmaceutical composition containing an effective amount of at least one compound of formula I according to at least one of claims 1-9.